Project Summary The objective in this proposal is to advance the understanding of the mechanisms through which parental divorce/separation and marital discord influence offspring alcohol use disorder (AUD) and related outcomes (e.g., earlier age at first drink and alcohol misuse). It is commonly thought that parental divorce/separation and parental marital discord have direct, pathogenic effects on offspring alcohol outcomes. Yet, there is a limited appreciation of the role of genetic factors in these associations, despite suggestive evidence that offspring exposed to parental marital problems also inherit AUD genetic predispositions, and that AUD genetic predispositions can sensitize individuals to the adverse effects of environmental stressors. This underscores the need to study the confluence of genetic factors and these common family adversities to understand their joint legacy on offspring alcohol outcomes. The goal here is to address this gap using data from two intergenerational, genetically-informative studies. The first is the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, a sample of European ancestry twins (N=9345, 45% female) recruited from birth records for whom direct psychiatric interview data were collected on all twins plus a subset of parents (N=1472, 58% female), with additional parental data collected via diagnostic psychiatric family history interviews with the twins. The second is the Collaborative Study on the Genetics of Alcoholism (N=11561, 53% female), a molecular genetic study of an ethnically diverse (69% European American, 31% African American) sample of families primarily recruited via treatment-seeking probands for whom psychiatric interview data were collected from all participants. These two samples are mutually informative in permitting examination of the generalizability and convergence of findings across different methods and populations. Guided by a bio- ecological framework, the aims are to: (1) examine the extent to which associations between parental divorce/separation, parental marital discord, and offspring alcohol outcomes reflect direct (i.e., ?causal?) effects versus shared genetic effects; and (2) examine whether offspring genetic factors predict variability in their responses to parental divorce/separation and parental marital discord. The results may have theoretical implications for the indirect, environmental pathways through which genetic risk for alcohol problems is transmitted in families (i.e., gene-environment correlation), as well as an understanding of how genetic influences confer sensitivity to familial stressors (i.e., gene-environment interaction). In turn, the results may inform clinicians? psychoeducation efforts to prevent alcohol misuse among offspring from families experiencing marital distress and divorce. More broadly, this work will contribute to the long-term goal of the Early Stage Investigator PI?s program of research to delineate how genetic factors and close relationship factors come together to influence the onset, persistence, and discontinuity of alcohol misuse.